title: Underactivation of the adiponectin-adiponectin receptor 1 axis in clear cell renal cell carcinoma: implications for progression.
abstract: Energy-sensing pathways, normally coordinated by 5' AMP-activated protein kinase (AMPK), are dysregulated in renal cell carcinoma (RCC). Obesity can accentuate the pre-existing pro-tumorigenic metabolic machinery in RCC cells through its associated obesogenic hormonal milieu, characterized by lower circulating levels of adiponectin. In RCC patients, low adiponectin levels associate clinically with more aggressive disease. We investigated the adiponectin signaling pathway in RCC, focusing on adiponectin receptor 1 (AdipoR1) and associated activation of AMPK. AdipoR1 protein in RCC and normal surrounding renal tissues was determined by Western blot analysis and immunohistochemistry. Anti-tumorigenic effects of adiponectin in RCC cells in vitro were investigated via VEGF and MMP ELISA and invasion assays. Using in vivo models of RCC, the effect of AdipoR1-knockdown (shRNA) on tumor latency, growth and dissemination were determined. AdipoR1 protein was significantly reduced in clear cell RCC specimens. Adiponectin treatment inhibited VEGF, MMP-2 and MMP-9 secretion and activity and invasive and migratory capacities of RCC cells. AMPKα1-knockdown (shRNA) attenuated adiponectin's effects. In cells stably expressing AdipoR1-specific shRNA, AMPK activation by adiponectin was significantly reduced compared to cells expressing control shRNA. In vivo, AdipoR1 knockdown increased the growth, dissemination and angiogenesis of RCC. These findings suggest that deficiencies in the entire adiponectin hormonal axis (the hormone and its receptor) result in underactivation of AMPK leading to increased angiogenic and invasive capacities of RCC. The established link between obesity and RCC can therefore be further explained by the adiponectin deficiency in obese individuals together with reduced AdipoR1 protein in RCC.
authors.affiliation: Division of Urology, Department of Surgery, McMaster University, Hamilton, ON, Canada.
authors.forename: Nir
authors.initials: N
authors.lastname: Kleinmann
authors.forename: Wilhelmina C M
authors.initials: WC
authors.lastname: Duivenvoorden
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Hopmans
authors.forename: Laura K
authors.initials: LK
authors.lastname: Beatty
authors.forename: Shengjun
authors.initials: S
authors.lastname: Qiao
authors.forename: Daniel
authors.initials: D
authors.lastname: Gallino
authors.forename: Sarka
authors.initials: S
authors.lastname: Lhotak
authors.forename: Dean
authors.initials: D
authors.lastname: Daya
authors.forename: Athanasios
authors.initials: A
authors.lastname: Paschos
authors.forename: Richard C
authors.initials: RC
authors.lastname: Austin
authors.forename: Jehonathan H
authors.initials: JH
authors.lastname: Pinthus
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D052242:Adiponectin / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology / Q000503:physiopathology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011494:Protein Kinases / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C475418:ADIPOR1 protein, human; D052242:Adiponectin; D054419:Receptors, Adiponectin; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D020782:Matrix Metalloproteinases